Role of melatonin in the induction and maintenance of sleep.

Pharmacokinetic studies of melatonin in young and elderly human volunteers, and the measurement of hypnotic effects in chicks under alternate light-dark or permanent light conditions, show that melatonin is a bioprecursor of hypnotic acetyl metabolites produced by the enzymatic acetylation of both melatonin and 2-oxomelatonin under the control of serotonin N-acetyltransferases (NATs), which are present in the pineal gland. The acetyl metabolite of melatonin, which we call carbo2, is an N-acetyl-β-carboline. The electroencephalographs (EEG) architecture of the sleep produced by this compound is similar to thai of physiological sleep, and is characterized by the significant proportion of slow-wave deep sleep and rapid eye movement sleep. This is in sharp contrast to the EEG sleep architecture observed with GABAergic (GABA, γ-aminobutyric acid) compounds. Since insomnia and sleep disorders are believed to be due to a lack of NAT enzymes in the pineal gland, a new therapeutic approach of sleep disorders by administration of such hypnotic acetyl metabolites of melatonin, or synthetic analogs thereof, can be en visaged.